Cytidine Deaminase As a Molecular Target in Cancer: an Insight

University of Texas Rio Grande Valley ScholarWorks @ UTRGV

Chemistry Faculty Publications and Presentations College of Sciences

8-21-2017

Cytidine deaminase as a molecular target in cancer: an insight

Claudia A. Almaraz

Debasish Bandyopadhyay The University of Texas Rio Grande Valley, [email protected]

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Recommended Citation Claudia A. Almaraz, et al. Cytidine deaminase as a molecular target in cancer: an insight†. Can Cell Microenviron 2017; 4: e1584. doi: 10.14800/ccm.1584.

This Article is brought to you for free and open access by the College of Sciences at ScholarWorks @ UTRGV. It has been accepted for inclusion in Chemistry Faculty Publications and Presentations by an authorized administrator of ScholarWorks @ UTRGV. For more information, please contact [email protected], [email protected]. Cancer Cell & Microenvironment 2017; 4: e1584. doi: 10.14800/ccm.1584; © 2017 by Claudia A. Almaraz, et al. http://www.smartscitech.com/index.php/ccm

REVIEW

Cytidine deaminase as a molecular target in cancer: an insight†

Claudia A. Almaraz, Debasish Bandyopadhyay

Department of Chemistry, The University of Texas-Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA

Correspondence: Debasish Bandyopadhyay E-mail: [email protected] Received: July 14, 2017 Published online: August 21, 2017 †A heartfelt tribute to the memory of Professor Asima Chatterjee, the legendary scientist-teacher-humanitarian, on the occasion of her birth centenary (1917-2017).

Cancer is one of the leading causes of death globally. Although more than 400 varieties of cancer have been reported, based on cell lines, still the actual reason of all types of cancer is not very clear. Several internal and external factors have been identified and the study is ongoing. Up to now about 73 proteins have been identified that are capable to influence directly various phases of cancer including mutation, cell proliferation, invasion, angiogenesis, and metastasis. Cytidine deaminase is one of the important proteins that is responsible for various types of cancer that includes gastric, liver, biliary tract, bladder, breast, pancreatic ductal adenocarcinoma (PDAC) and so on. Two excellent inhibitors of cytidine deaminase are commercially available. A brief overview is presented in this advanced review. Any omission is completely unintentional. Keywords: Cytidine deaminase; Cancer; Inhibitor; APOBEC; AID To cite this article: Claudia A. Almaraz, et al. Cytidine deaminase as a molecular target in cancer: an insight†. Can Cell Microenviron 2017; 4: e1584. doi: 10.14800/ccm.1584. Copyright: © 2017 The Authors. Licensed under a Creative Commons Attribution 4.0 International License which allows users including authors of articles to copy and redistribute the material in any medium or format, in addition to remix, transform, and build upon the material for any purpose, even commercially, as long as the author and original source are properly cited or credited.

Introduction process that removes an amine group from the molecule by means of hydrolysis. This occurs in the liver or kidneys and Cancer is the second leading cause of death worldwide usually the enzyme will remove only one amine group from and about 8.8 million people died in cancer only in 2015. any extra proteins. Cytidine deaminases (CDA) are the Late-stage determination and limited accessibility in members of multisubunit enzymes (allosteric enzymes) diagnosis/pathological evaluations, and subsequent family that are found in every mammal. It is encased in treatment, particularly in the low- and middle-income human tissues, organs, and it is encoded in the CDA gene. countries, are very frequent. It is imperative to mention that The CDA gene encodes this enzyme that is involved in [1] about 1 in 6 deaths around the world is due to cancer . On pyrimidine salvaging. The protein that is then encoded, forms the other hand, appropriate knowledge and understanding of a homotetramer that causes a catalyzation that in itself is an molecular targets are an important part in the battle against irreversible hydrolytic deamination of cytidine and cancer. In fact a huge number of proteins play crucial role in deoxycytidine to uridine and lastly deoxyuridine. There are different stages of cancer starting from DNA mutation, several deaminases that are responsible to maintain of the [2] invasion, angiogenesis, metastasis and so on . Deaminases cellular pyrimidine pool, this particular one is one of them [3]. are enzymes that catalyze deamination of a molecule, a

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Discussion

It is well-known that cancer starts primarily by developing certain mutations in DNA. DNA contains certain genes that activate and signal the corresponding cell what to do and how to do it. The only issue here is when those instructions inadvertently create errors that hinder the natural cellular processes. Cell mutations may happen in multiple ways; it can be by birth and develop sometimes thereafter or it be caused due to external factors. There are over 400 types of cancers that exist and with that multiple types of pathways attempt to defeat them before they metastasize, with the most Figure 1. Commercially available CDA inhibitors Zebularine and Tetrahydrouridine (THU). common CDA-dependent types include, but are not limited to, bladder, breast, colon, lung, melanoma, prostate, thyroid opening up new possibilities to treat cancer[11]. APOBEC3 kidney, endometrial, pancreatic and non-Hodgkin’s and AID boost immune response by mutating immune or lymphoma. Studies have linked cytidine deaminase to viral genes. Because of their genome-mutating activities activation of mutation that creates certain cancers. APBOEC these proteins are capable to promote tumorigenesis. AID is a (catalytic polypeptide-like), a family of evolutionarily 198 amino acid DNA-editing enzyme that deaminates dC to conserved CDAs, are involved in several significant dU in ssDNA. AID promotes hypermutation in biochemical processes in human body such as antibody immunoglobulin (Ig) loci that induces genome-wide diversification/maturation, restriction of viral infection, and mutations, subsequent breaking of double-strand leads tumor generation of somatic mutations. APBOEC is wide spread in formation [12-18]. various human cancers which mentions the correlation to 14 different types of cancer found through a genome and exome Human CDA plays major role to catalyze metabolic data set criteria. APOBEC3 protein families, a DNA cytidine processing of nucleoside-type anticancer and antiviral agents. deaminase, are up-regulated in several types of cancer. The Accordingly, it is a promising target for the development of application to these criteria was applied to 954,247 mutations small molecule anticancer adjuvants. Two well-known in 2,680 exomes. The APOBEC pattern of mutation was commercially available cytidine deaminase inhibitors are present in bladder, cervical, breast, lung, and head and neck shown in Figure 1. Zebularine binds to the active site as cancer. It was found to reach 68% of the mutation patterns in covalent hydrates and inhibits in vitro DNA-methylation and some samples. Multiple studies have concluded the similar subsequently tumor growth is inhibited in vivo. On the other findings with correlation between CDA and cancer. CDA in hand, the orally active drug THU modulates antiproliferative this instance was concluded to be a necessary expression for effects. the development of cancer in animal models as well as those found in human skin cancers such as melanoma, and head Conclusion and neck cancer. It has been reported that mutation demonstrated by an oncogene or tumor suppressor gene Cytidine deaminases are prevalent in many organisms and expression that when heavily accumulated the mutation this in human CDA plays major role to develop certain types of would result in cancer. The cytidine deaminase family, is an cancer. Although several studies have had been conducted essential enzyme for somatic hyper mutation and additionally around the globe still more precise investigation is obligatory for class-switch recombination of antibody genes. It was also to reveal a better picture. Development of more effective reported that there is involvement of cytidine deaminases the inhibitors with higher potency (to the malignant cells) and development of cancers in the gastrointestinal tract, lower toxicity (to the normal cells) are timely and mammary gland, and prostate[4-10]. Interestingly, challenging to encounter cancer. downregulation of cytidine deaminase was reported for the Conflicting interests patients with Bloom syndrome, a genetic disease related to a strong predisposition to a wide range of cancers. Recently it The authors have declared that no conflict of interests has been reported that CDA-deficient tumor cells can be exists. specifically targeted with small molecule antitumor drugs,

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